{"id":"https://openalex.org/W7214307653","doi":"https://doi.org/10.64898/2026.09.22.753441","title":"TopoFlow: Evolutionarily Conditioned Flow Matching for Protein Conformational Ensemble Generation","display_name":"TopoFlow: Evolutionarily Conditioned Flow Matching for Protein Conformational Ensemble Generation","publication_year":2026,"publication_date":"2026-09-24","ids":{"openalex":"https://openalex.org/W7214307653","doi":"https://doi.org/10.64898/2026.09.22.753441"},"language":"en","primary_location":{"id":"doi:10.64898/2026.09.22.753441","doi":"https://doi.org/10.64898/2026.09.22.753441","is_oa":true,"landing_page_url":"https://doi.org/10.64898/2026.09.22.753441","pdf_url":"https://www.biorxiv.org/content/biorxiv/early/2026/09/24/2026.09.22.753441.full.pdf","source":{"id":"https://openalex.org/S4306402567","display_name":"bioRxiv (Cold Spring Harbor Laboratory)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I2750212522","host_organization_name":"Cold Spring Harbor Laboratory","host_organization_lineage":["https://openalex.org/I2750212522"],"host_organization_lineage_names":[],"type":"repository"},"license":null,"license_id":null,"version":"submittedVersion","is_accepted":false,"is_published":false,"raw_source_name":"bioRxiv","raw_type":"posted-content"},"volume":null,"type":"preprint","is_traditional":true,"indexed_in":["crossref"],"open_access":{"is_oa":true,"oa_status":"green","oa_url":"https://www.biorxiv.org/content/biorxiv/early/2026/09/24/2026.09.22.753441.full.pdf","any_repository_has_fulltext":true},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5102413087","display_name":"Xinguang Yang","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I55712492","display_name":"Zhejiang University of Technology","ror":"https://ror.org/02djqfd08","country_code":"CN","type":"education","lineage":["https://openalex.org/I55712492"]}],"countries":["CN"],"is_corresponding":false,"raw_author_name":"Xinguang Yang","raw_affiliation_strings":["College of Information Engineering, Zhejiang University of Technology, 288 Liuhe Road, 310023 Hangzhou, China"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"College of Information Engineering, Zhejiang University of Technology, 288 Liuhe Road, 310023 Hangzhou, China","institution_ids":["https://openalex.org/I55712492"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5124374818","display_name":"Xinyue cui","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I55712492","display_name":"Zhejiang University of Technology","ror":"https://ror.org/02djqfd08","country_code":"CN","type":"education","lineage":["https://openalex.org/I55712492"]}],"countries":["CN"],"is_corresponding":false,"raw_author_name":"Xinyue Cui","raw_affiliation_strings":["College of Information Engineering, Zhejiang University of Technology, 288 Liuhe Road, 310023 Hangzhou, China"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"College of Information Engineering, Zhejiang University of Technology, 288 Liuhe Road, 310023 Hangzhou, China","institution_ids":["https://openalex.org/I55712492"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5124325261","display_name":"Xuhui Li","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I55712492","display_name":"Zhejiang University of Technology","ror":"https://ror.org/02djqfd08","country_code":"CN","type":"education","lineage":["https://openalex.org/I55712492"]}],"countries":["CN"],"is_corresponding":false,"raw_author_name":"Xuhui Li","raw_affiliation_strings":["College of Information Engineering, Zhejiang University of Technology, 288 Liuhe Road, 310023 Hangzhou, China"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"College of Information Engineering, Zhejiang University of Technology, 288 Liuhe Road, 310023 Hangzhou, China","institution_ids":["https://openalex.org/I55712492"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5146053808","display_name":"Dongliang Hou","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I55712492","display_name":"Zhejiang University of Technology","ror":"https://ror.org/02djqfd08","country_code":"CN","type":"education","lineage":["https://openalex.org/I55712492"]}],"countries":["CN"],"is_corresponding":false,"raw_author_name":"Dongliang Hou","raw_affiliation_strings":["College of Information Engineering, Zhejiang University of Technology, 288 Liuhe Road, 310023 Hangzhou, China"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"College of Information Engineering, Zhejiang University of Technology, 288 Liuhe Road, 310023 Hangzhou, China","institution_ids":["https://openalex.org/I55712492"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5058113371","display_name":"Suhui Wang","orcid":"https://orcid.org/0000-0003-4839-956X","observed_orcids":["https://orcid.org/0000-0003-4839-956X"]},"institutions":[{"id":"https://openalex.org/I55712492","display_name":"Zhejiang University of Technology","ror":"https://ror.org/02djqfd08","country_code":"CN","type":"education","lineage":["https://openalex.org/I55712492"]}],"countries":["CN"],"is_corresponding":false,"raw_author_name":"Suhui Wang","raw_affiliation_strings":["College of Information Engineering, Zhejiang University of Technology, 288 Liuhe Road, 310023 Hangzhou, China"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"College of Information Engineering, Zhejiang University of Technology, 288 Liuhe Road, 310023 Hangzhou, China","institution_ids":["https://openalex.org/I55712492"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5152816706","display_name":"Tengyu Xie","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I55712492","display_name":"Zhejiang University of Technology","ror":"https://ror.org/02djqfd08","country_code":"CN","type":"education","lineage":["https://openalex.org/I55712492"]}],"countries":["CN"],"is_corresponding":false,"raw_author_name":"Tengyu Xie","raw_affiliation_strings":["College of Information Engineering, Zhejiang University of Technology, 288 Liuhe Road, 310023 Hangzhou, China"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"College of Information Engineering, Zhejiang University of Technology, 288 Liuhe Road, 310023 Hangzhou, China","institution_ids":["https://openalex.org/I55712492"]}]},{"author_position":"last","author":{"id":"https://openalex.org/A5152896149","display_name":"Guijun Zhang","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I55712492","display_name":"Zhejiang University of Technology","ror":"https://ror.org/02djqfd08","country_code":"CN","type":"education","lineage":["https://openalex.org/I55712492"]}],"countries":["CN"],"is_corresponding":true,"raw_author_name":"Guijun Zhang","raw_affiliation_strings":["College of Information Engineering, Zhejiang University of Technology, 288 Liuhe Road, 310023 Hangzhou, China"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"College of Information Engineering, Zhejiang University of Technology, 288 Liuhe Road, 310023 Hangzhou, China","institution_ids":["https://openalex.org/I55712492"]}]}],"institutions":[],"countries_distinct_count":1,"institutions_distinct_count":1,"corresponding_author_ids":["https://openalex.org/A5152896149"],"corresponding_institution_ids":["https://openalex.org/I55712492"],"apc_list":null,"apc_paid":null,"fwci":null,"has_fulltext":true,"cited_by_count":0,"citation_normalized_percentile":null,"cited_by_percentile_year":null,"biblio":{"volume":null,"issue":null,"first_page":null,"last_page":null},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T10044","display_name":"Protein Structure and Dynamics","score":0.9994999766349792,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},"topics":[{"id":"https://openalex.org/T10044","display_name":"Protein Structure and Dynamics","score":0.9994999766349792,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T10211","display_name":"Computational Drug Discovery Methods","score":9.999999747378752e-05,"subfield":{"id":"https://openalex.org/subfields/3002","display_name":"Drug Discovery"},"field":{"id":"https://openalex.org/fields/30","display_name":"Pharmacology, Toxicology and Pharmaceutics"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T11162","display_name":"Enzyme Structure and Function","score":9.999999747378752e-05,"subfield":{"id":"https://openalex.org/subfields/1315","display_name":"Structural Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/protein-conformational-ensembles","display_name":"protein conformational ensembles","score":0.9459999799728394},{"id":"https://openalex.org/keywords/flow-matching","display_name":"flow matching","score":0.9290000200271606},{"id":"https://openalex.org/keywords/multiple-sequence-alignment","display_name":"multiple sequence alignment","score":0.6819999814033508},{"id":"https://openalex.org/keywords/variational-autoencoder","display_name":"variational autoencoder","score":0.8679999709129333},{"id":"https://openalex.org/keywords/protein-flexibility","display_name":"protein flexibility","score":0.5040000081062317},{"id":"https://openalex.org/keywords/conformational-heterogeneity","display_name":"conformational heterogeneity","score":0.7390000224113464},{"id":"https://openalex.org/keywords/molecular-dynamics-trajectories","display_name":"molecular dynamics trajectories","score":0.5350000262260437},{"id":"https://openalex.org/keywords/chemical-shifts","display_name":"chemical shifts","score":0.703000009059906},{"id":"https://openalex.org/keywords/small-angle-x-ray-scattering","display_name":"small-angle X-ray scattering","score":0.9900000095367432},{"id":"https://openalex.org/keywords/ensemble-generation","display_name":"ensemble generation","score":0.3970000147819519}],"concepts":[{"id":"https://openalex.org/C2777936996","wikidata":"https://www.wikidata.org/wiki/Q17148461","display_name":"Conformational ensembles","level":3,"score":0.7009999752044678},{"id":"https://openalex.org/C168568712","wikidata":"https://www.wikidata.org/wiki/Q909999","display_name":"Radius of gyration","level":3,"score":0.5993000268936157},{"id":"https://openalex.org/C184898388","wikidata":"https://www.wikidata.org/wiki/Q1435712","display_name":"Pairwise comparison","level":2,"score":0.5332000255584717},{"id":"https://openalex.org/C47701112","wikidata":"https://www.wikidata.org/wiki/Q735188","display_name":"Protein structure","level":2,"score":0.4408000111579895},{"id":"https://openalex.org/C59593255","wikidata":"https://www.wikidata.org/wiki/Q901663","display_name":"Molecular dynamics","level":2,"score":0.4212000072002411},{"id":"https://openalex.org/C121864883","wikidata":"https://www.wikidata.org/wiki/Q677916","display_name":"Statistical physics","level":1,"score":0.4092000126838684},{"id":"https://openalex.org/C154945302","wikidata":"https://www.wikidata.org/wiki/Q11660","display_name":"Artificial intelligence","level":1,"score":0.38280001282691956},{"id":"https://openalex.org/C98763669","wikidata":"https://www.wikidata.org/wiki/Q176645","display_name":"Markov chain","level":2,"score":0.36410000920295715},{"id":"https://openalex.org/C101738243","wikidata":"https://www.wikidata.org/wiki/Q786435","display_name":"Autoencoder","level":3,"score":0.3601999878883362},{"id":"https://openalex.org/C41008148","wikidata":"https://www.wikidata.org/wiki/Q21198","display_name":"Computer science","level":0,"score":0.35850000381469727},{"id":"https://openalex.org/C2775981520","wikidata":"https://www.wikidata.org/wiki/Q17156992","display_name":"Protein dynamics","level":3,"score":0.34540000557899475},{"id":"https://openalex.org/C165064840","wikidata":"https://www.wikidata.org/wiki/Q1321061","display_name":"Matching (statistics)","level":2,"score":0.33399999141693115},{"id":"https://openalex.org/C186060115","wikidata":"https://www.wikidata.org/wiki/Q30336093","display_name":"Biological system","level":1,"score":0.33340001106262207},{"id":"https://openalex.org/C45942800","wikidata":"https://www.wikidata.org/wiki/Q245652","display_name":"Ensemble learning","level":2,"score":0.3190999925136566},{"id":"https://openalex.org/C11413529","wikidata":"https://www.wikidata.org/wiki/Q8366","display_name":"Algorithm","level":1,"score":0.3179999887943268},{"id":"https://openalex.org/C152769699","wikidata":"https://www.wikidata.org/wiki/Q410814","display_name":"Protein design","level":3,"score":0.3158000111579895},{"id":"https://openalex.org/C50311922","wikidata":"https://www.wikidata.org/wiki/Q898535","display_name":"Statistical ensemble","level":4,"score":0.31529998779296875},{"id":"https://openalex.org/C121332964","wikidata":"https://www.wikidata.org/wiki/Q413","display_name":"Physics","level":0,"score":0.3107999861240387},{"id":"https://openalex.org/C14036430","wikidata":"https://www.wikidata.org/wiki/Q3736076","display_name":"Function (biology)","level":2,"score":0.3091999888420105},{"id":"https://openalex.org/C33923547","wikidata":"https://www.wikidata.org/wiki/Q395","display_name":"Mathematics","level":0,"score":0.2935999929904938},{"id":"https://openalex.org/C46686674","wikidata":"https://www.wikidata.org/wiki/Q466303","display_name":"Boosting (machine learning)","level":2,"score":0.2919999957084656},{"id":"https://openalex.org/C2778112365","wikidata":"https://www.wikidata.org/wiki/Q3511065","display_name":"Sequence (biology)","level":2,"score":0.26030001044273376},{"id":"https://openalex.org/C2992240565","wikidata":"https://www.wikidata.org/wiki/Q856529","display_name":"Protein evolution","level":3,"score":0.25999999046325684},{"id":"https://openalex.org/C66746571","wikidata":"https://www.wikidata.org/wiki/Q1134833","display_name":"ENCODE","level":3,"score":0.2547999918460846}],"mesh":[],"locations_count":1,"locations":[{"id":"doi:10.64898/2026.09.22.753441","doi":"https://doi.org/10.64898/2026.09.22.753441","is_oa":true,"landing_page_url":"https://doi.org/10.64898/2026.09.22.753441","pdf_url":"https://www.biorxiv.org/content/biorxiv/early/2026/09/24/2026.09.22.753441.full.pdf","source":{"id":"https://openalex.org/S4306402567","display_name":"bioRxiv (Cold Spring Harbor Laboratory)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I2750212522","host_organization_name":"Cold Spring Harbor Laboratory","host_organization_lineage":["https://openalex.org/I2750212522"],"host_organization_lineage_names":[],"type":"repository"},"license":null,"license_id":null,"version":"submittedVersion","is_accepted":false,"is_published":false,"raw_source_name":"bioRxiv","raw_type":"posted-content"}],"best_oa_location":{"id":"doi:10.64898/2026.09.22.753441","doi":"https://doi.org/10.64898/2026.09.22.753441","is_oa":true,"landing_page_url":"https://doi.org/10.64898/2026.09.22.753441","pdf_url":"https://www.biorxiv.org/content/biorxiv/early/2026/09/24/2026.09.22.753441.full.pdf","source":{"id":"https://openalex.org/S4306402567","display_name":"bioRxiv (Cold Spring Harbor Laboratory)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I2750212522","host_organization_name":"Cold Spring Harbor Laboratory","host_organization_lineage":["https://openalex.org/I2750212522"],"host_organization_lineage_names":[],"type":"repository"},"license":null,"license_id":null,"version":"submittedVersion","is_accepted":false,"is_published":false,"raw_source_name":"bioRxiv","raw_type":"posted-content"},"sustainable_development_goals":[],"study_designs":[],"awards":[{"id":"https://openalex.org/G3455588047","display_name":null,"funder_award_id":"2025C01190","funder_id":"https://openalex.org/F4320321001","funder_display_name":"National Natural Science Foundation of China"},{"id":"https://openalex.org/G6882808339","display_name":null,"funder_award_id":"2023R5248","funder_id":"https://openalex.org/F4320321001","funder_display_name":"National Natural Science Foundation of China"},{"id":"https://openalex.org/G7271978295","display_name":null,"funder_award_id":"62203389","funder_id":"https://openalex.org/F4320321001","funder_display_name":"National Natural Science Foundation of China"}],"funders":[{"id":"https://openalex.org/F4320321001","display_name":"National Natural Science Foundation of China","ror":"https://ror.org/01h0zpd94"}],"has_content":{"grobid_xml":true,"pdf":true},"content_urls":{"pdf":"https://content.openalex.org/works/W7214307653.pdf","grobid_xml":"https://content.openalex.org/works/W7214307653.grobid-xml"},"referenced_works_count":50,"referenced_works":["https://openalex.org/W1604487056","https://openalex.org/W1959608418","https://openalex.org/W2014425795","https://openalex.org/W2059790242","https://openalex.org/W2067236515","https://openalex.org/W2070359441","https://openalex.org/W2102461176","https://openalex.org/W2128328398","https://openalex.org/W2151581834","https://openalex.org/W2161151688","https://openalex.org/W2265800909","https://openalex.org/W2493341306","https://openalex.org/W2583686612","https://openalex.org/W2609870844","https://openalex.org/W2626778328","https://openalex.org/W2786672974","https://openalex.org/W2808746463","https://openalex.org/W2917395421","https://openalex.org/W2949342052","https://openalex.org/W2950954328","https://openalex.org/W2977366709","https://openalex.org/W2978202256","https://openalex.org/W3010272512","https://openalex.org/W3089408272","https://openalex.org/W3131204112","https://openalex.org/W3177828909","https://openalex.org/W3184400502","https://openalex.org/W3213738679","https://openalex.org/W4252684946","https://openalex.org/W4281790889","https://openalex.org/W4303647933","https://openalex.org/W4310945739","https://openalex.org/W4310957810","https://openalex.org/W4320040108","https://openalex.org/W4327550249","https://openalex.org/W4379919077","https://openalex.org/W4387595626","https://openalex.org/W4388627063","https://openalex.org/W4388870515","https://openalex.org/W4389285741","https://openalex.org/W4391673325","https://openalex.org/W4393249720","https://openalex.org/W4396723792","https://openalex.org/W4408220597","https://openalex.org/W4408504447","https://openalex.org/W4411428671","https://openalex.org/W4412165572","https://openalex.org/W4412449676","https://openalex.org/W4415329770","https://openalex.org/W7124731324"],"related_works":["https://openalex.org/W7164881729","https://openalex.org/W4408293717","https://openalex.org/W4391673325","https://openalex.org/W4414842369","https://openalex.org/W7220706611","https://openalex.org/W7126219719","https://openalex.org/W7169799031","https://openalex.org/W6967074438","https://openalex.org/W4383483775","https://openalex.org/W4406681183"],"abstract_inverted_index":{"Abstract":[0],"Proteins":[1],"function":[2],"through":[3,70,167],"dynamic":[4],"conformational":[5,31,46,83],"ensembles":[6,17],"rather":[7],"than":[8],"a":[9,55,71,177],"single":[10],"static":[11],"structure,":[12],"yet":[13],"accurately":[14],"modeling":[15],"these":[16],"remains":[18],"challenging.":[19],"Here,":[20],"we":[21],"introduce":[22],"TopoFlow,":[23,166],"an":[24],"evolutionarily":[25],"conditioned":[26],"flow-matching":[27],"framework":[28],"for":[29,98,180],"protein":[30,82,187],"ensemble":[32,84,160],"generation.":[33,85,161],"TopoFlow":[34,93,128],"uses":[35],"evolutionary":[36,150,171],"representations":[37,65,151],"from":[38,54],"multiple":[39],"sequence":[40],"alignments":[41],"(MSAs)":[42],"to":[43,59,75,118,124,159],"encode":[44],"global":[45],"heterogeneity.":[47],"It":[48],"combines":[49],"this":[50,121],"with":[51,132],"structural":[52,153,173],"variables":[53,155],"variational":[56],"autoencoder":[57],"(VAE)":[58],"capture":[60],"local":[61],"flexibility.":[62],"These":[63],"complementary":[64,157],"are":[66],"then":[67],"adaptively":[68],"fused":[69],"conditional":[72],"modulation":[73],"module":[74],"construct":[76],"unified":[77],"conditioning":[78],"features":[79],"that":[80,148,165],"guide":[81],"On":[86],"the":[87,95,149],"ATLAS":[88],"molecular":[89],"dynamics":[90],"(MD)":[91],"benchmark,":[92],"improved":[94],"Jensen\u2013Shannon":[96],"metrics":[97],"pairwise":[99],"distances":[100],"(JS-PwD),":[101],"radius":[102],"of":[103,170],"gyration":[104],"(JS-Rg),":[105],"and":[106,114,139,152,172,184],"time-lagged":[107],"independent":[108],"components":[109],"(JS-TIC)":[110],"by":[111],"10.73%,":[112],"5.78%":[113],"7.75%,":[115],"respectively,":[116],"relative":[117],"BioEmu.":[119],"Notably,":[120],"performance":[122],"generalizes":[123],"experiment-based":[125],"evaluation,":[126],"where":[127],"exhibits":[129],"strong":[130],"agreement":[131],"experimental":[133],"observables,":[134],"including":[135],"chemical":[136],"shifts":[137],"(CS)":[138],"small-angle":[140],"X-ray":[141],"scattering":[142],"(SAXS).":[143],"Ablation":[144],"analyses":[145],"further":[146],"indicated":[147],"latent":[154,174],"contributed":[156],"information":[158],"Our":[162],"results":[163],"suggest":[164],"its":[168],"integration":[169],"information,":[175],"offers":[176],"promising":[178],"strategy":[179],"generating":[181],"structurally":[182],"plausible":[183],"conformationally":[185],"informative":[186],"ensembles.":[188]},"counts_by_year":[],"updated_date":"2026-11-09T13:22:03.289127","created_date":"2026-09-26T00:00:00"}
